Metal-free synthesis of isatin oximes: Via radical coupling reactions of oxindoles with t -BuONO in water

Article abstract of DOI:10.1039/c7ob01235g

A metal-free method for the synthesis of isatin oximes was developed through the radical coupling reactions of oxindoles with t-BuONO. This protocol provides a practical and environmentally benign method for the construction of C-N bonds in water at room temperature without using any other reagents. The advantages of this strategy are its mild reaction conditions and clean procedure.

Full text of DOI:10.1039/c7ob01235g

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Biomolecular Chemistry
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Metal-free synthesis of isatin oximes via radical
coupling reactions of oxindoles with t-BuONO
in water†
Cite this: Org. Biomol. Chem., 2017,
15, 5254
Received 19th May 2017,
Accepted 6th June 2017
Wen-Ting Wei, * Wen-Ming Zhu, Wei-Wei Ying, Yi Wu, Yi-Ling Huang and
Hongze Liang
DOI: 10.1039/c7ob01235g
rsc.li/obc
A metal-free method for the synthesis of isatin oximes was devel- the Lewis acid catalyzed cyclization reaction of isonitroso-
oped through the radical coupling reactions of oxindoles with acetanilides.6 However, the use of stoichiometric amounts of a
t-BuONO. This protocol provides a practical and environmentally hydroxylamine salt and an equal equivalent of a base or Lewis
benign method for the construction of C–N bonds in water at acid greatly restricts their application in organic chemistry.
room temperature without using any other reagents. The advan- Therefore, a green and highly efficient method is still required.
tages of this strategy are its mild reaction conditions and clean
Recently, methods have been developed to build complex
molecules via a radical coupling reaction between two inacti-
vated C–H bonds.7 Compared with traditional coupling reac-
tions, this protocol avoids the pre-functionalization of C–H
bonds, thus exhibiting step and atom economy. In this regard,
the construction of the C–N bond has been attracting increas-
ing interest due to its ubiquitous presence in pharmaceutical
and materials science.8 One efficient example was reported by
Wang and co-workers, who documented a palladium-catalyzed
direct conversion of methyl arenes into aromatic nitriles
(Scheme 1a).9 In 2015, Lu and co-workers reported a radical
coupling reaction to construct the C–N bonds by the use of
Cu(OAc)2 as a catalyst and N-hydroxyphthalimide (NHPI) as an
additive at 80 °C (Scheme 1b).10 However, both of the protocols
require the use of a metal catalyst and an external oxidant, as
well as elevated temperature to promote the reaction.
procedure.
Introduction
Isatin oximes constitute the central core of a wide variety of
bioactive compounds and pharmaceutical molecules that
exhibit potential biological activities (Fig. 1, e.g., anticonvul-
sant, antiviral, and anticancer).1 On the other hand, an oxime
group is a valuable synthetic building block, which can be
widely used in the dehydration reaction,2 1,3-dipolar addition
reaction,3 and Beckmann rearrangement reaction.4 The most
common methods for obtaining an isatin oxime framework
are through the base promoted condensation reaction of a
carbonyl compound with hydroxylamine hydrochloride5 and
Hence, from the environmental point of view, establishing
a green and simple route to isatin oxime synthesis through the
radical coupling reaction has attracted increasing attention.11
Moreover, the use of water as the reaction medium for the
radical coupling reaction, especially without the addition of
any metal catalysts and external oxidants at room temperature,
Fig. 1 Representative bioactive compounds or drugs containing isatin
oximes.
School of Materials Science and Chemical Engineering, Ningbo University,
Ningbo 315211, China. E-mail: weiwenting@nbu.edu.cn; Fax: +86(0574)87600784
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c7ob01235g
Scheme 1 C–N bond formation using t-BuONO as a partner via radical
coupling reactions.
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Table 2 Examples of radical coupling reactionsa
is still a challenge. All of these pioneering studies encouraged
us to explore a clean and efficient methodology for the
synthesis of isatin oximes. As a continuing interest in radical
coupling reactions,12 we present our preliminary experimental
results of a metal-free synthesis of isatin oximes via radical
coupling reactions of oxindoles with t-BuONO in water at room
temperature (Scheme 1c).
Results and discussion
To verify our hypothesis, the reaction of oxindole 1a and
t-BuONO 2a was chosen as a model reaction to optimize
the conditions by using diverse solvents and the results are
summarized in Table 1. The coupling product 3a was only
produced in 5% isolated yield when the reaction was carried
out in 1,4-dioxane at room temperature for 18 h (entry 1).
Therefore, a preliminary study was implemented with the aim
of searching an appropriate solvent to promote the reaction
between 1a and 2a. H2O was chosen due to reports revealing
its friendly applications in such radical coupling reactions.
Changing the solvent to 1,4-dioxane–H2O (1.6 mL : 0.2 mL)
afforded 3a in 37% isolated yield (entry 2). Encouraged by this
result, different volume ratios of 1,4-dioxane–H2O were evalu-
ated for this reaction (entries 3–5): we found that the yield of
3a increased along with the increased loading of H2O. When
H2O was used as the sole solvent, the yield of 3a rose to 96%.
Screening the loading of t-BuONO revealed that the amount of
t-BuONO affected the reaction, and the reaction with 4.0 equiv.
of t-BuONO was revealed as the most effective loading (entries
5–7). Moreover, no further improvement was observed at
higher temperature (40 °C, entry 8). It is noteworthy that a
good yield is still achieved by using the 1 gram scale of 1a by
prolonging the reaction time to 48 h (entry 9). Thus, based on
the above experiments, we determined the optimized con-
ditions to be 1a (0.3 mmol), t-BuONO (4.0 equiv.), and H2O
(2 mL) at room temperature in air for 18 h.
a Reaction conditions: 1 (0.3 mmol), 2a (1.2 mmol) and H2O (2 mL) in
air at r.t. for 18 h. b 0.2 mL of 1,4-dioxane was added.
Having optimized the reaction conditions, we next investi-
gated the scope of the radical coupling reaction by different
oxindoles with t-BuONO 2a. As shown in Table 2, a variety
of oxindoles, bearing both electron-rich substituents (R =
Me, Bn, Ph) and electron-poor substituents (R = Boc) at the
N-substituted position, reacted smoothly with 2a, affording the
corresponding isatins 3b–3e in good to excellent yields. The un-
protected oxindole gave the desired product 3a in 96% yield.
Notably, N-Me, N-Bn and N-Ph substituents can be tolerated in
this radical coupling reaction (products 3b–3d), giving the
corresponding products in 75%, 62%, and 89% yields respect-
ively. Moreover, the N-Boc substituted substrate was also
reacted effectively with 2a to give the corresponding product 3e
in 45% yield. We then turned our attention to an aryl moiety,
as shown in Table 1, and a range of oxindoles, with both
electron-donating groups and electron-withdrawing groups on
an aryl ring, were viable in this transformation. The aryl ring
with an electron-donating group (3f) displayed a lower reac-
tivity than those bearing electron-withdrawing groups (3g, 3h
and 3i). Notably, Cl and Br substituents can be tolerated in the
radical coupling reaction, thereby facilitating additional modi-
fications at the halogenated positions. To our delight, this
method was successfully applied to multiple oxindoles, and
these substrates were smoothly converted to the corresponding
isatins 3j–3n in moderate yields. Unfortunately, the substrate
N,2-diphenylacetamide was not suitable for the radical coup-
ling reaction under the current conditions.
Table 1 Optimization of reaction conditionsa
Entry
Solvent (mL)
Yield (%)
1
2
3
4
1,4-Dioxane (2.0)
1,4-Dioxane (1.6)–H2O (0.2)
1,4-Dioxane (1.6)–H2O (0.4)
1,4-Dioxane (1.6)–H2O (0.8)
H2O (2.0)
H2O (2.0)
H2O (2.0)
5
37
53
58
96
71
95
97
89
5
6b
7c
8d
9e
H2O (2.0)
H2O (2.0)
As shown in Scheme 2, two radical inhibitors (4.0 equiv.),
including 2,2,6,6-tetramethylpiperidinooxy (TEMPO) and 2,6-
di-tert-butyl-4-methyl phenol (BHT), were added to the radical
a Reaction conditions: 1a (0.3 mmol), 2a (1.2 mmol) and solvent in air
at r.t. for 18 h. b 2a (3.0 equiv.). c 2a (5.0 equiv.). d At 40 °C. e 1a
(7.52 mmol, 1 g) for 48 h.
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with ethyl acetate and washed with brine. The organic layer
was extracted with ethyl acetate, and the combined organic
layers were dried over anhydrous sodium sulfate. After the
removal of sodium sulfate through filtration, the solution was
concentrated under reduced pressure, and the mixture was
purified by flash column chromatography over silica gel
(hexane/ethyl acetate) to afford the desired products 3.
Scheme 2 Control experiments.
Acknowledgements
This research is sponsored by the research funds of NBU
(No. ZX2016000706), the Foundation of Ningbo University
(No. XYL17009), and the K. C. Wong Magna Fund in Ningbo
University.
Notes and references
Scheme 3 Plausible mechanism.
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radical process.
Based on the above-mentioned control experiments and
previous mechanistic studies,9,10,13,14
a possible reaction
pathway has been proposed in Scheme 3. Initially, t-BuONO is
split into the t-BuO radical and NO radical.13 Subsequently,
the t-BuO radical abstracted a hydrogen atom from the
oxindole 1 to generate the t-BuOH and oxindole radical A.9
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reaction occurred to furnish intermediate B which was fol-
lowed by the isomerization to afford the final product isatin
oxime 3.10
Conclusions
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synthesis method for the conversion of oxindoles into isatin
oximes. This radical coupling reaction provides a green and
clean procedure for the construction of C–N bonds. Most
importantly, the use of t-BuONO as a nitrogen source, and
H2O as the solvent makes this new transformation sustainable
and practical. Further studies on the development of radical
coupling reactions are currently underway in our laboratory.
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Typical experimental procedure for the radical coupling
reaction
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